CAR T Cell Therapy for Brain Cancer
Recruiting in Palo Alto (17 mi)
Overseen byBilal Omer, MD
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Baylor College of Medicine
Must not be taking: Immunotherapy, Colony-stimulating factors
Disqualifiers: Pregnancy, Breastfeeding, Other risk factors, others
No Placebo Group
Trial Summary
What is the purpose of this trial?In this study, there are two treatment groups called Cohort 1 and Cohort 2. Cohort 1 is for patients with diffuse midline glioma, high grade glioma, diffuse intrinsic pontine glioma, medulloblastoma, or another rare brain cancer that expresses GD2. Cohort 2 is for patients with a type of cancer called progressive pontine diffuse midline glioma (DMG), high grade glioma or diffuse intrinsic pontine glioma that expresses GD2.
Because there is no standard treatment at this time, patients are asked to volunteer in a gene transfer research study using special immune cells called T cells. T cells are a type of white blood cell that help the body fight infection.
This research study combines two different ways of fighting cancer: antibodies and T cells. Both antibodies and T cells have been used to treat cancer patients. They have shown promise but have not been strong enough to cure most patients.
Researchers have found from previous research that they can put a new antibody gene into T cells that will make them recognize cancer cells and kill them. GD2 is a protein found on several different cancers. Researchers testing brain cancer cells found that many of these cancers also have GD2 on their surface.
In a study for neuroblastoma in children, a gene called a chimeric antigen receptor (CAR) was made from an antibody that recognizes GD2. This gene was put into the patients own T cells and given back to 11 patients. The cells did grow for a while but started to disappear from the blood after 2 weeks. The researchers think that if T cells are able to last longer they may have a better chance of killing tumor cells.
In this study, a new gene will be added to the GD2 T cells that can cause the cells to live longer. T cells need substances called cytokines to survive. The gene C7R has been added that gives the cells a constant supply of cytokine and helps them to survive for a longer period of time.
In other studies using T cells researchers found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. This is called lymphodepletion and it will allow the T cells to expand and stay longer in the body and potentially kill cancer cells more effectively.
After treating 11 patients, the largest safe dose of GD2-CAR T cells given in the vein (IV) was determined. Going forward, we will combine IV infusions with infusions directly into the brain through the Ommaya reservoir or programmable VP shunt. The goal is to find the largest safe dose of GD2-C7R T cells that can be administered in this way.
Patients will now be assigned to Cohort 1 and 2 based on their tumor type with different dose levels for each cohort.
The GD2.C7R T cells are an investigational product not approved by the FDA.
The purpose of this study is to combine infusions into the vein in the first treatment cycle with infusions directly into the cerebrospinal fluid (CSF) in the brain (intracerebroventricularly) through the ommaya reservoir or programmable VP shunt for the second infusion cycle and possibly additional infusions after that. The goal is to find the largest safe dose of GD2-C7R T cells that can be administered in this way, and additionally to evaluate how long they can be detected in the blood and CSF and what affect they have on brain cancer.
Do I need to stop my current medications to join the trial?
The trial requires you to stop any concurrent anti-cancer therapy at least three half-lives before treatment. You also cannot have received any other forms of immunotherapy within 42 days before the investigational agent or colony-stimulating factors within 14 days prior to lymphodepletion. The protocol does not specify about other medications, so please consult with the trial team for more details.
What data supports the idea that CAR T Cell Therapy for Brain Cancer is an effective treatment?
The available research shows that CAR T Cell Therapy targeting GD2 has shown promise in treating brain cancer. In one study, three out of four patients with a specific type of brain cancer showed improvement after receiving this treatment. Another study found that this therapy could effectively target and kill cancer cells in laboratory models of glioblastoma, a severe brain cancer. Additionally, when compared to other methods, delivering the treatment directly into the brain significantly increased survival time without side effects. These findings suggest that CAR T Cell Therapy could be a promising option for treating certain brain cancers.
12345What safety data is available for CAR T Cell Therapy targeting GD2 in brain cancer?
The safety data for GD2-targeted CAR T cell therapy in brain cancer is mixed. Studies indicate that GD2-specific CAR T cells have been generally well tolerated in clinical trials, with no dose-limiting toxicities reported in some cases. However, there are concerns about neurotoxicity, as seen in preclinical models where GD2 CAR T cells induced fatal neurotoxicity in a costimulatory domain-dependent manner. In another study, peritumoral neuroinflammation during antitumor activity led to lethal hydrocephalus in some animal models. Therefore, while the therapy shows promise, careful monitoring and management are necessary to mitigate potential neurotoxic effects.
13678Is the treatment (C7R)-GD2.CART cells promising for brain cancer?
Yes, the treatment (C7R)-GD2.CART cells is promising for brain cancer. It uses the body's immune system to target and destroy cancer cells, showing potential in treating aggressive brain tumors like glioblastoma and diffuse midline gliomas. Early trials have shown positive results in targeting specific proteins on tumor cells, and it could be transformative for certain childhood brain cancers.
19101112Eligibility Criteria
This trial is for children and young adults aged 1 to 21 with specific brain cancers that have a protein called GD2 on their surface. These include newly diagnosed or recurrent tumors like diffuse midline glioma, high-grade glioma, medulloblastoma, and others. Participants need measurable disease on MRI and a functional score indicating they can perform daily activities at least half the time.Inclusion Criteria
My tumor is smaller than 5 cm.
Procurement
My tumor was between 5 and 5.5 cm but was surgically reduced in size.
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Lymphodepletion Chemotherapy
Patients receive cyclophosphamide and fludarabine (or clofarabine) to prepare for T cell infusion
3 days
1 visit (in-person)
T Cell Infusion and Monitoring
Patients receive GD2-C7R T cells via IV and/or ICV infusion and are monitored for side effects
4 weeks
Hospital stay for up to 5 days post-infusion, with monitoring in Houston for up to 4 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
15 years
Visits at weeks 1, 2, 3, 4, 6, 8, then at months 3, 6, 9, 12, and biannually for 4 years, then annually
Participant Groups
The study tests genetically modified T cells (a type of immune cell) designed to last longer in the body by adding a gene called C7R. This helps them fight cancer more effectively. The trial involves two methods of infusing these cells: directly into the brain (ICV) and into the vein (IV), after chemotherapy to improve their survival.
2Treatment groups
Experimental Treatment
Group I: C7R-GD2.CAR T cells (Cohort 2)Experimental Treatment1 Intervention
The dose level for autologous cell C7R-GD2.CAR T cell immunotherapy administered via intravenous (IV) infusion was determined in the initial phase of the protocol. The standard IV dosing is 10 million cells/m2 with lymphodepletion chemotherapy.
Group II: C7R-GD2.CAR T cells (Cohort 1)Experimental Treatment1 Intervention
The dose level for autologous cell C7R-GD2.CAR T cells administered via intravenous (IV) infusion was determined in the initial phase of the protocol. The standard IV dose is 10 million cells/m2 with lymphodepletion chemotherapy.
In this subsequent phase of the study, the safe dosing levels for autologous cell C7R-GD2.CAR T cell immunotherapy administered intracerebroventricularly (ICV) via ommaya reservoir or programmable VP shunt in combination with subsequent IV doses will be determined.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Texas Children's HospitalHouston, TX
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Who Is Running the Clinical Trial?
Baylor College of MedicineLead Sponsor
Faris FoundationCollaborator
Center for Cell and Gene Therapy, Baylor College of MedicineCollaborator
Violet Foundation for Pediatric Brain CancerCollaborator
The Faris FoundationCollaborator
ChadTough Defeat DIPG FoundationCollaborator
References
Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. [2022]Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10, and recent results suggest benefit in central nervous system malignancies11-13. Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2. Anti-GD2 CAR T cells incorporating a 4-1BBz costimulatory domain 14 demonstrated robust antigen-dependent cytokine generation and killing of DMG cells in vitro. In five independent patient-derived H3-K27M+ DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2lo glioma cells. To date, GD2-targeted CAR T cells have been well tolerated in clinical trials15-17. Although GD2-targeted CAR T cell administration was tolerated in the majority of mice bearing orthotopic xenografts, peritumoral neuroinflammation during the acute phase of antitumor activity resulted in hydrocephalus that was lethal in a fraction of animals. Given the precarious neuroanatomical location of midline gliomas, careful monitoring and aggressive neurointensive care management will be required for human translation. With a cautious multidisciplinary clinical approach, GD2-targeted CAR T cell therapy for H3-K27M+ diffuse gliomas of pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers.
GD2-Targeting CAR T Cells Show Promise in H3K27M-Mutated Gliomas. [2022]Three out of four patients treated with GD2-targeting CAR T cells showed radiographic and clinical improvement.
Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma. [2023]This study aimed to validate whether infusion of GD2-specific fourth-generation safety-designed chimeric antigen receptor (4SCAR)-T cells is safe and whether CAR-T cells exert anti-glioblastoma (GBM) activity.
GD2 CAR T cells against human glioblastoma. [2021]Glioblastoma is the most malignant primary brain tumor and is still in need of effective medical treatment. We isolated patient-derived glioblastoma cells showing high GD2 antigen expression representing a potential target for CAR T strategy. Data highlighted a robust GD2 CAR antitumor potential in 2D and 3D glioblastoma models associated with a significant and CAR T-restricted increase of selected cytokines. Interestingly, immunosuppressant TGF β1, expressed in all co-cultures, did not influence antitumor activity. The orthotopic NOD/SCID models using primary glioblastoma cells reproduced human histopathological features. Considering still-conflicting data on the delivery route for targeting brain tumors, we compared intracerebral versus intravenous CAR T injections. We report that the intracerebral route significantly increased the length of survival time in a dose-dependent manner, without any side effects. Collectively, the proposed anti-GD2 CAR can counteract human glioblastoma potentially opening a new therapeutic option for a still incurable cancer.
B7-H3 as a Novel CAR-T Therapeutic Target for Glioblastoma. [2020]Glioblastoma (GBM) remains one of the most malignant primary tumors in adults, with a 5-year survival rate less than 10% because of lacking effective treatment. Here, we aimed to explore whether B7-H3 could serve as a novel therapeutic target for GBM in chimeric antigen receptor (CAR) T cell therapy. In this study, a CAR targeting B7-H3 was constructed and transduced into T cells by lentivirus. Antitumor effects of B7-H3-specific CAR-T cells were assessed with primary and GBM cell lines both in vitro and in vivo. Our results indicated that B7-H3 was positively stained in most of the clinical glioma samples, and its expression levels were correlated to the malignancy grade and poor survival in both low-grade glioma (LGG) and GBM patients. Specific antitumor functions of CAR-T cells were confirmed by cytotoxic and ELISA assay both in primary glioblastoma cells and GBM cell lines. In the orthotropic GBM models, the median survival of the CAR-T-cell-treated group was significantly longer than that of the control group. In conclusion, B7-H3 is frequently overexpressed in GBM patients and may serve as a therapeutic target in CAR-T therapy.
Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma. [2021]The ability to utilize preclinical models to predict the clinical toxicity of chimeric antigen receptor (CAR) T cells in solid tumors is tenuous, thereby necessitating the development and evaluation of gated systems. Here we found that murine GD2 CAR-T cells, specific for the tumor-associated antigen GD2, induce fatal neurotoxicity in a costimulatory domain-dependent manner. Meanwhile, human B7H3 CAR-T cells exhibit efficacy in preclinical models of neuroblastoma. Seeking a better CAR, we generated a SynNotch gated CAR-T, GD2-B7H3, recognizing GD2 as the gate and B7H3 as the target. GD2-B7H3 CAR-T cells control the growth of neuroblastoma in vitro and in metastatic xenograft mouse models, with high specificity and efficacy. These improvements come partly from the better metabolic fitness of GD2-B7H3 CAR-T cells, as evidenced by their naïve T-like post-cytotoxicity oxidative metabolism and lower exhaustion profile.
CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. [2022]Targeting disialoganglioside (GD2) on neuroblastoma (NB) with T cells expressing a first-generation chimeric antigen receptor (CAR) was safe, but the cells had poor expansion and long-term persistence. We developed a third-generation GD2-CAR (GD2-CAR3) and hypothesized that GD2-CAR3 T cells (CARTs) would be safe and effective. This phase 1 study enrolled relapsed or refractory NB patients in three cohorts. Cohort 1 received CART alone, cohort 2 received CARTs plus cyclophosphamide and fludarabine (Cy/Flu), and cohort 3 was treated with CARTs, Cy/Flu, and a programmed death-1 (PD-1) inhibitor. Eleven patients were treated with CARTs. The infusions were safe, and no dose-limiting toxicities occurred. CARTs were detectable in cohort 1, but the lymphodepletion induced by Cy/Flu increased circulating levels of the homeostatic cytokine interleukin (IL)-15 (p = 0.003) and increased CART expansion by up to 3 logs (p = 0.03). PD-1 inhibition did not further enhance expansion or persistence. Antitumor responses at 6 weeks were modest. We observed a striking expansion of CD45/CD33/CD11b/CD163+ myeloid cells (change from baseline, p = 0.0126) in all patients, which may have contributed to the modest early antitumor responses; the effect of these cells merits further study. Thus, CARTs are safe, and Cy/Flu can further increase their expansion.
Clinical Predictors of Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy. [2021]Chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory hematologic malignant neoplasm causes severe neurologic adverse events ranging from encephalopathy and aphasia to cerebral edema and death. The cause of neurotoxicity is incompletely understood, and its unpredictability is a reason for prolonged hospitalization after CAR T-cell infusion.
Chimeric Antigen Receptor T-Cell Therapy: Updates in Glioblastoma Treatment. [2022]Glioblastoma multiforme (GBM) are the most common and among the deadliest brain tumors in adults. Current mainstay treatments are insufficient to treat this tumor, and therefore, more effective therapies are desperately needed. Immunotherapy, which takes advantage of the body's natural defense mechanism, is an exciting emerging field in neuro-oncology. Adoptive cell therapy with chimeric antigen receptor (CAR) T cells provides a treatment strategy based on using patients' own selected and genetically engineered cells that target tumor-associated antigens. These cells are harvested from patients, modified to target specific proteins expressed by the tumor, and re-introduced into the patient with the goal of destroying tumor cells. Here, we review the history of CAR T-cell therapy, and describe the characteristics of various generations of CAR T therapies, and the challenges inherent to treatment of GBM. Finally, we describe recent and current CAR T clinical trials designed to combat GBM.
CAR T Cells. [2021]Chimeric antigen receptor T (CAR-T) cells, an immunotherapy that demonstrates marked success in treatment of hematologic malignancies, are an emergent therapeutic for patients with glioblastoma (GBM). GBM CAR-T trials have focused on targeting well-characterized antigens in the pathogenesis of GBM. Early stage trials demonstrate initial success in terms of safety and tolerability. There is preliminary evidence of antitumor activity and localization of the CAR-T product to tumoral sites. There are mixed results regarding patient outcomes. Ongoing GBM CAR-T trials will target novel antigens, explore CAR-T combination therapy, design multivalent CAR constructs, and assess the impact of lymphodepletion before CAR-T delivery.
CAR T-cells to treat brain tumors. [2023]Tremendous success using CAR T therapy in hematological malignancies has garnered significant interest in developing such treatments for solid tumors, including brain tumors. This success, however, has yet to be mirrored in solid organ neoplasms. CAR T function has shown limited efficacy against brain tumors due to several factors including the immunosuppressive tumor microenvironment, blood-brain barrier, and tumor-antigen heterogeneity. Despite these considerations, CAR T-cell therapy has the potential to be implemented as a treatment modality for brain tumors. Here, we review adult and pediatric brain tumors, including glioblastoma, diffuse midline gliomas, and medulloblastomas that continue to portend a grim prognosis. We describe insights gained from different preclinical models using CAR T therapy against various brain tumors and results gathered from ongoing clinical trials. Furthermore, we outline the challenges limiting CAR T therapy success against brain tumors and summarize advancements made to overcome these obstacles.
Future development of chimeric antigen receptor T cell therapies for patients suffering from malignant glioma. [2023]Chimeric antigen receptor (CAR) T cell therapy has been successful in some haematologic malignancies, but the central nervous system (CNS) presents unique obstacles to its use against tumours arising therein. This review discusses recent improvements in the delivery and design of these cells to improve the efficacy and safety of this treatment against malignant gliomas.